PROJECT SUMMARY Acute kidney injury (AKI) is a major cause of patient morbidity and mortality and appears to be a substantial risk factor for future progression to chronic kidney disease (CKD). According to NIDDK statistics, roughly 14% of Americans exhibit indications of CKD and 20% of all Medicare spending goes towards it management. Slowing AKI-to-CKD progression, or identifying those patients most at risk for future CKD following AKI, is currently not possible largely due to a fundamental gap in understanding of the pathogenesis of AKI-to-CKD transition. Inflammation-associated lymphangiogenesis (LAG) is critical in regulating inflammation through fluid, macromolecule (cytokines and antigens), and immune cell transport. While LAG has been identified in a host of kidney diseases, reports have been mostly correlative. The long-term goal is to identify the mechanisms by which lymphatics regulate tissue biology in chronic inflammatory disease. The overall objective in this application is to identify the roles of the renal lymphatic vasculature during kidney injury and exploit the induction of enhanced LAG as a potential therapy. The central hypothesis is that increasing renal lymphatics provides a route of immune cell clearance while also potentially regulating solute transport. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: 1) Determine how renal LAG affects inflammation and renal function in AKI; and 2) Determine the mechanisms by which renal LAG reduces AKI-to- CKD progression; and 3) Determine the impact of enhancing renal lymphatic density on CKD. Under the first aim, 3 models of AKI with diverse pathophysiologies will be used to identify how lymphatic density changes with AKI and whether expanding lymphatics using KidVD mice, a genetic model of kidney-specific LAG, can limit the AKI inflammatory response. Preliminary data suggest increased LAG protects against AKI. In the second aim, how LAG alters the progression of AKI-to-CKD will be determined. Additionally, how changes in interstitial pressures and mineral metabolism in the kidney with increased LAG during sodium and phosphate challenge may provide a novel mechanism for AKI protection. For the third aim, therapeutic strategies to induce LAG once CKD is established will be tested in each of the 3 renal pathologies. The proposed research is innovative, in the applicant?s opinion, because it addresses and specifically targets the lymphatic vasculature of the kidney to improve kidney function and inflammation upon AKI. New potential therapies and biomarkers are expected to result from this work. The proposed research is significant because it is expected to identify previously unknown mechanisms of kidney inflammatory regulation and transport functions. Ultimately, understanding the mechanisms by which lymphatic vessels regulate kidney function and health has the potential to be transformative to AKI response and treatment and in remediating the current epidemic of incurable chronic kidney disease.